I-Journal ye-Neuroscience, I-14 ngo-Novemba 2007, 27(46): 12700-12706; ikhonkco: 10.1523 / 3371-JNEUROSCI.07.2007
Nora D. Volkow1,2, UGene-Jack Wang3, UFrank Telang2, UJoanna S. Fowler3, UJohn Logan3, UMillard Jayne2, Ewe Ma2, Kith Pradhan4, yaye UChristopher Wong3
Abstract
Ixabiso lembuyekezo (imivuzo yendalo kunye neziyobisi) inxulunyaniswa nokunyuka kwe-dopamine kwi-nucleus accumbens kwaye iyahluka njengomsebenzi womxholo. I-prefrontal cortex iye yabandakanyeka kumxholo wokuxhomekeka kwimbuyekezo kunye nexabiso eliphezulu elilungisiweyo lamachiza analo kumlutha, nangona iindlela zokusebenza zingaqondwa kakuhle. Apha sivavanya i-hypothesis yokuba i-prefrontal cortex ilawula ixabiso lemivuzo ngokumodareyitha ukunyuka kwe-dopamine kwi-nucleus accumbens kunye nokuba lo mmiselo uphazamisekile kwizifundo ezikhobokileyo. Sisebenzise i-positron emission tomography ukuvavanya umsebenzi we-prefrontal cortex (ukulinganisa ingqondo ye-glucose metabolism kunye [18F]fluorodeoxyglucose) kunye ne-dopamine yonyuka (ilinganiswa nge [11C]raclopride, kunye noD2/D3 I-receptor ligand enezibophelelo ezithintekayo kwi-endogenous dopamine) eyenziwa yi-methylphenidate yeziyobisi ezivuselelayo kwii-20 zolawulo kunye ne-20 enxilisayo enxilisayo, uninzi lwabo lutshaya. Kuzo zonke izifundo, i-methylphenidate yonyusa kakhulu i-dopamine kwi-striatum. Kwi-ventral striatum (apho i-nucleus accumbens ikhona) nakwi-putamen, ukonyuka kwe-dopamine kwanxulunyaniswa neziphumo ezinomvuzo ze-methylphenidate (ukuthanda iziyobisi kunye nokuphakama) kwaye zazithotywe kakhulu kwizinxila (i-70 kunye ne-50% ephantsi kunolawulo, ngokulandelelana). Kulawulo, kodwa hayi kwiziselo ezinxilisayo, i-metabolism kwi-orbitofrontal cortex (ingingqi ebandakanyekayo kwi-salience attribution) yayanyaniswa kakubi nokunyuka kwe-methylphenidate-induced dopamine kwi-ventral striatum. Ezi ziphumo ziyangqinelana ne-hypothesis yokuba i-cortex ye-orbitofrontal imodareyitha ixabiso lemivuzo ngokulawula ubukhulu bokwanda kwe-dopamine kwi-ventral striatum kwaye ukuphazamiseka kwalo mgaqo kunokubangela ukuncipha kovakalelo kwimivuzo kwizifundo ezikhobokileyo.
intshayelelo
Ukonyuka kwe-dopamine (DA) kudityaniswa neempendulo ezomelezayo kwizinto zokusetyenziswa kakubi kubandakanya utywala (Koob et al., 1998), kodwa indlela (s) esisiseko sokukhobokisa ayicacanga kangako. Kukholelwa ukuba ukusetyenziswa kweziyobisi ezingapheliyo kubangela utshintsho oluguquguqukayo kwimimandla (iisekethe) eziguqulwe yi-DA ephantsi kwe-neurobiology yokulutha (URobbins no-Everitt, i-2002; Nestler, 2004). Phakathi kwezi, i-prefrontal cortex iyanda ukubonwa njengedlala indima ephambili kumlutha (UJentsch noTylor, i-1999). Ngokukodwa okufanelekileyo ziziphumo ze-cortical zangaphambili kwindawo ye-ventral tegmental (VTA) kunye ne-nucleus accumbens (NAc), edlala indima ebalulekileyo ekulawuleni indlela yokudubula yeeseli ze-DA kunye nokukhululwa kwe-DA, ngokulandelanayo (IGariano kunye neeGroves, i-1988; UMurase et al., 1993). Ewe, izifundo zangaphambi kweklinikhi ziye zabhala utshintsho kule ndlela kunye nokuvezwa kweziyobisi ezingapheliyo, eziye zacingelwa ukuba ziphantsi kokulahleka kolawulo lokuthatha iziyobisi olubonisa ukuba likhoboka (I-White et al., 1995; Kalivas, 2004).
Injongo yolu phononongo yayikukuvavanya ukulawulwa komsebenzi we-DA yobuchopho nge-cortex yangaphambili ekunxileni. Ukuvavanya umsebenzi we-DA yobuchopho, sasebenzisa i-positron emission tomography (PET) kunye [11C] umdyarho webala (DA D2/D3 i-radioligand ye-receptor enezibophelelo ezinovakalelo kukhuphiswano yi-DA engapheliyo) (Volkow et al., 1994a) ngaphambi nangemva komngeni kunye ne-intravenous methylphenidate (MP) kwaye uthelekise iimpendulo phakathi kwe-20 yotywala obunxilisayo kunye ne-20 yokulawula okunempilo. Sasebenzisa i-MP njengomngeni we-pharmacological kuba inyusa i-DA ngokuvala abathuthi be-DA (DATs) kwaye ngoko ivumela uvavanyo olungathanga ngqo lomsebenzi weseli ye-DA (Volkow et al., 2002). Ukuvavanya umsebenzi we-prefrontal cortex, silinganisele ingqondo ye-glucose metabolism, esebenza njengophawu lomsebenzi wobuchopho (Sokoloff et al., 1977), usebenzisa i-PET kunye [18F]fluorodeoxyglucose (FDG). Iingqikelelo zethu ezisebenzayo yayikukuba kwizifundo ezinxilisayo, ukulawulwa komsebenzi wobuchopho be-DA nge-prefrontal cortex kuya kuphazamiseka kwaye ngewunciphise umsebenzi we-DA. Kwakhona ngenxa yokuba ukunyuka kweDA okubangelwa yi-MP kunxulunyaniswa neziphumo ezinomvuzo (Volkow et al., 1999), siphinde sacinga ukuba ukunciphisa ukukhutshwa kwe-DA kwiinxila kuya kukhokelela ekuphazameni kwembono ezimeleyo yeziphumo eziyolisayo zeMP.
Impahla nenkqubo
I zifundo.
Izifundo zotywala zamadoda ezingamashumi amabini kunye ne-20 yolawulo olusempilweni yamadoda yaphononongwa. Abanxilisayo baye bafunwa kwiindawo zonyango kunye nezibhengezo. 1 Table ibonelela ngeempawu zabantu kunye nekliniki yezifundo. Ubuncinci ababini oogqirha baye benza udliwano-ndlebe nezigulana ukuqinisekisa ukuba ziyadibana I-Diagnostic and Statistical Manual of Disabilities (DSM), uhlaziyo lwesine, i-criteria yokuxilonga utywala, kunye nodliwano-ndlebe oluqhelekileyo olusemgangathweni usebenzisa i-DSM criteria. Iikhrayitheriya zokubandakanywa nazo zazifuna ukuba babe nesihlobo sokuqala esinxilisayo. Izifundo zazingabandakanywa ukuba zinembali yokusetyenziswa gwenxa kweziyobisi okanye umlutha (ngaphandle kotywala kunye ne-nicotine). Iinqobo zokukhutshwa nazo zibandakanya imbali yesifo sengqondo (ngaphandle kokuxhomekeka kotywala) okanye isifo se-neurological, iimeko zonyango ezinokuguqula umsebenzi we-cerebral (okt, i-cardiovascular, i-endocrinological, i-oncological, okanye i-autoimmune izifo), ukusetyenziswa kwangoku kwamayeza amiselweyo okanye angaphezulu. , kunye / okanye ukuxhatshazwa kwentloko kunye nokulahlekelwa yingqondo> 30 min. Zonke izifundo zazinexhala likaHamilton (IHamilton, i-1959) kunye nokudandatheka kukaHamilton (IHamilton, i-1960) amanqaku <19 kwaye kwafuneka ukuba uyekile ukusela utywala ubuncinane kwi-30 d phambi kophononongo. Ulawulo lwafunyaniswa kwizibhengezo kumaphephandaba asekuhlaleni; iindlela zokukhutshelwa ngaphandle ngaphandle kwesibonelelo sokuxhomekeka etywaleni okanye ukusetyenziswa gwenxa ziyafana nezo zabantu abanxilileyo. Ukongezelela, izifundo zokulawula zazingabandakanywa ukuba zinembali yentsapho yokusela utywala. Zonke izifundo ziye zaxilongwa ngokwasemzimbeni, ngokwasengqondweni, nakwimithambo-luvo. Izikrini zeziyobisi zenziwa ngeentsuku zezifundo ze-PET ukuba zingabandakanyi ukusetyenziswa kweziyobisi zengqondo. Izifundo zayalelwa ukuba ziyeke nayiphi na i-counter-counter-counter 2 iiveki ngaphambi kwe-PET scan, kwaye izilawuli ziyalelwe ukuba ziyeke ukusela utywala kwiveki ngaphambi kwe-PET scan. Ukutya kunye neziselo (ngaphandle kwamanzi) ziye zayekwa ubuncinane kwiiyure ezi-4 ngaphambi kokuba icuba lipheliswe ubuncinane kwiiyure ezi-2 phambi kophononongo. Olu pho nonongo luvunyiwe yiBhodi yokuHlola iZiko kwiBrookhaven National Laboratory, kwaye imvume ebhaliweyo enolwazi ifunyenwe kuzo zonke izifundo.
Iimpawu zabantu kunye nekliniki yolawulo kunye nezifundo ezinxilisayo
Amanyathelo okuziphatha kunye nentliziyo.
Amanqaku aphantsi (1-10) kwiimpembelelo zeziyobisi zabhalwa ngaphambi nangemizuzu eyi-27 emva kwe-placebo okanye ulawulo lweMP (Wang et al., 1997). Ezi ngxelo zizimeleyo zeziphumo zamachiza zibonakaliswe ukuba zithembekile kwaye ziyahambelana kwizifundo zonke (UFischman kunye noFoltin, ngo-1991). Izinga lentliziyo kunye noxinzelelo lwegazi kwajongwa ngaphambi nangexesha emva kwe-placebo okanye ulawulo lweMP.
Iskena.
Izifundo ze-PET zenziwa nge-Siemens (Iselin, NJ) i-tomograph ye-HR + (isisombululo, 4.5 × 4.5 × 4.5 mm ububanzi obugcweleyo kwisiqingatha esiphezulu) kwimodi emithathu-dimensional. Zonke izifundo zigqibe iiscan ezimbini zenziwe nge [11C]raclopride, kunye ne-19 yolawulo kunye ne-19 yabanxila bagqiba ukuskena okwesithathu okwenziwe nge-FDG. Ukuskena kwagqitywa kwithuba le-2 d, kwaye i-odolo yenziwe ngokungaqhelekanga. Iindlela zipapashelwe [11C]raclopride (Volkow et al., 1993a) kunye ne-FDG (Wang et al., 1993). Ukwenzela i [11C] i-raclopride scans, esinye sezikena ezibini zenziwa emva kwe-placebo ye-intravenous (3 cc ye-saline), kwaye enye yenziwa emva kwe-intravenous MP (0.5 mg / kg), eyanikwa i-1 min phambi [11C]inaliti yeraclopride. Uphononongo yayiluyilo lwe-crossover eyodwa eyimfama. Izikena ezinamandla zaqalwa ngoko nangoko emva kokutofwa kwe-4–10 mCi ye [11C]raclopride (umsebenzi okhethekileyo, 0.5-1.5 Ci / μm ekupheleni kwebhombu) kwaye yafunyanwa iyonke ye-54 min. Igazi le-Arterial lifunyenwe kulo lonke inkqubo yokulinganisa ukuxinwa okungaguqukiyo [11C]raclopride kwiplasma njengoko kuchaziwe ngaphambili (Volkow et al., 1993a). Kwi-FDG, amanyathelo ayenziwa kwiimeko ezisisiseko (akukho vuselelo), kwaye i-20 min emission scan yaqalwa i-35 min emva kokutofa kwe-4-6 mCi ye-FDG, kwaye igazi le-arterial lisetyenziselwa ukulinganisa i-FDG kwi-plasma. Ngethuba lexesha lokuthatha, izifundo zahlala kwindawo yokulala kunye namehlo avulekileyo kwigumbi elimnyama, kwaye ingxolo yayigcinwa incinci. Amazinga e-metabolic ayenziwa kusetyenziswa ukongezwa kwemodeli ye-Sokoloff (Iiphelps et al., 1979).
Uhlalutyo lomfanekiso.
Ukwenzela i [11C]imifanekiso yeraclopride, iingingqi zomdla (ROIs) zafunyanwa ngqo kwi [11C]imifanekiso yeraclopride njengoko kuchaziwe ngaphambili (Volkow et al., 1994a). Ngokufutshane, sikhethe i-ROI kwimifanekiso eshwankathelweyo (imifanekiso eshukumayo ethatyathwe kwi-10 ukuya kwi-54 min) eyaye yahlaliswa ecaleni kwenqwelomoya ye-intercommisural apho sakhetha imimandla kwi-caudate (CDT), i-putamen (PUT), i-ventral striatum (VS), kunye ne-cerebellum. . Le mimandla ke ngoko yaqikelelwa kwizikena eziguquguqukayo ukufumana ugxininiso lwe-C-11 ngokuchasene nexesha, ezithi zisetyenziswe ukubala K1 (ukuthutha rhoqo ukusuka kwi-plasma ukuya kwizicubu) kunye nomthamo wokusabalalisa (i-DV), ehambelana nokulinganisa ukulingana komlinganiselo woxinaniso lwezicubu ukuya kwi-plasma yoxinaniso kwi-CDT, i-PUT, kunye ne-VS usebenzisa ubuchule bokuhlalutya umzobo kwiinkqubo ezibuyiselwa umva (Logan et al., 1990). Umlinganiselo we-DV kwi-striatum ukuya kwi-cerebellum, ehambelana nayo Bmax''/Kd+ 1 (Kd'kunye Bmax’ ziluncedo kwi vivo Ubukho be-neurotransmitter ye-endogenous kunye ne-nonspecific binding), yasetyenziswa njengoqikelelo lwe-D2/D3 ukufumaneka kwe-receptor (Logan et al., 1990). Iziphumo zeMP kwi [11C]i-raclopride ebophelelayo ilinganiswe njengotshintsho lwepesenti kwi Bmax''/Kd' ukusuka kwi-placebo (inguqu exhomekeke).
Kwimifanekiso ye-metabolic, sikhuphe i-ROI sisebenzisa indlela yotsalo oluzenzekelayo njengoko kuchaziwe ngaphambili kunye nesampuli (1) imimandla echongiweyo yangaphambili [i-orbitofrontal cortex (OFC), i-cingulate gyrus (CG), i-dorsolateral prefrontal], kuba izifundo zangaphambili zibonise ukuba balawula ukukhululwa kweDA; (2) imimandla ye-striatal (CDT, PUT, VS), kuba ezi njongo eziphambili zeetheminali zeDA; (3) imimandla ye-limbic (i-amygdala, i-hippocampus, i-insula), kuba ikwaziitheminali ze-DA; kunye (4) nethalamic, temporal, parietal, occipital, kunye nemimandla yecerebellar, esayiphatha njengemimandla yolawulo (Volkow et al., 2006). Ngokufutshane, siqale senza imaphu yemifanekiso yemetabolism kwi-MNI (Montreal Neurological Institute) indawo yobuchopho esemgangathweni ukuphelisa iyantlukwano kubuchopho bomntu ngamnye. Ukwenza izibalo ze-ROI, sivelise imephu egubungela zonke ii-voxels ezihambelanayo zommandla onikiweyo ngokulandela ulungelelwaniso kwi-software ye-Talairach Daemon (UCollins et al., 1995; I-lancaster et al., 2000) kumfanekiso we-FDG PET.
Uhlalutyo lweenkcukacha manani.
Iziphumo zeMP ku K1 kunye noD2/D3 ukufumaneka kwe-receptor (Bmax''/Kd’) kunye nomahluko phakathi kwamaqela akwisiseko kunye nokuphendula kwiMP zavavanywa nge-ANOVA enye into ephakathi kwesihloko (ulawulo vs izinxila) kunye nenye ngaphakathi kwesihloko (i-placebo vs MP). Ngeposi t iimvavanyo zisetyenziselwe ukufumanisa ukuba yeyiphi imiqathango eyahlukayo. Ukuvavanya umanyano phakathi kweenguqu ezenziwe yiMP kwi Bmax''/Kd' (ukuxhomekeka okuguquguqukayo) kwi-CDT, i-PUT, kunye ne-VS kunye ne-metabolism yengqondo yengingqi, senze i-Pearson imveliso yomzuzwana uhlalutyo lokulungelelaniswa kwemilinganiselo ye-metabolic. Ukuvavanya iingqikelelo ezintathu eziphambili zophononongo (1) ezikulawulo kodwa hayi kwimetabolism yotywala kwimimandla yangaphambili [CG, OFC, kunye ne-dorsolateral prefrontal cortex (DLPFC)] iya kunxulunyaniswa notshintsho olwenziwe yiMP Bmax''/Kd’ (utshintsho oluxhomekeke), (2) iMP ebangele utshintsho Bmax''/Kd′ inokuba ncinane kumakhoboka otywala kunolawulo, kwaye (3) iyatshintsha Bmax''/Kd′ kwi-VS iyakunxulunyaniswa neziphumo ezinomvuzo zeMP kwaye ke amanqaku "okuthanda iziyobisi" kunye "nokuphakama" kuya kuba sezantsi kwizinxila kunolawulo, sibeka inqanaba lokubaluleka p < 0.05. Kuhlalutyo lokuhlola ukuvavanya ulungelelwaniso phakathi kotshintsho kwi Bmax''/Kd’ (inguqu exhomekeke kuyo) kunye nemetabolism kwi-11 ROI engazange ibe yi-priori echazwe, sibeka ukubaluleka p < 0.005. Ukuqinisekisa ukuba ulungelelwaniso lubonisa umsebenzi wengingqi endaweni yomsebenzi opheleleyo wemetabolism, sikwavavanye ulungelelwaniso lwemilinganiselo yemetabolism yommandla eqhelekileyo (ingingqi yemetabolism/ingqondo epheleleyo). Ukwahluka kunxulumano phakathi kwamaqela kwavavanywa kusetyenziswa uvavanyo olupheleleyo lweziganeko zokuhlehla.
Kuba kwizifundo zangaphambili sibone unxibelelwano phakathi kwemilinganiselo yesiseko ye-D2/D3 ukufumaneka kwe-receptor kunye ne-prefrontal metabolism kwi-cocaine kunye nabaxhaphazi be-methamphetamine (Volkow et al., 1993b, 2001), siye savavanya olu lungelelwaniso ukufumanisa ukuba ngaba unxibelelwano olufanayo lwenzekile kwizifundo ezinxilisayo (ukubaluleka kwamiselwa p <0.05).
iziphumo
Izigxina zePlasma zeMP
Uxinzelelo lwe-plasma (kwi-nanograms nge-millimeter nganye) aluzange luhluke phakathi kokulawula kunye nezifundo ezinxilisayo kwi-10 min (116 ± 26 vs 107 ± 16, ngokulandelanayo), i-30 min (85 ± 25 vs 76 ± 12), okanye i-45 min (65 ± 15) vs 59 ± 11). Ugxininiso lwe-Plasma MP aluzange luhambelane notshintsho olwenziwe yiMP Bmax''/Kd'.
Iimpendulo zokuziphatha kwi-MP
Kuwo omabini amaqela, MP kakhulu (p <0.005) inyuse amanqaku kwiingxelo zokuziva ngathi siziyobisi, ukuba phezulu, ukungazinzi, ukuvuseleleka, ukulunga kweziyobisi, ukuthanda iziyobisi, ukungathandi iziyobisi, umnqweno wotywala, kunye nomnqweno wecuba (2 Table). Isiphumo sokusebenzisana sasibalulekile kuninzi lweengxelo ezizimeleyo zeziphumo zeziyobisi (ngaphandle kokungazinzi kunye nomnqweno wotywala) (2 Table). Ngeposi t Iimvavanyo zibonise ukuba iziphumo zeMP zinkulu kakhulu kulawulo kunezinxila eziphezulu (p <0.003), ivuselelwe (p <0.003), yiva ichiza (p <0.004), iziyobisi zilungile (p <0.04), kunye nokuthanda iziyobisi (p <0.04) kwaye babebakhulu kwiinxila zomnqweno wecuba (p <0.002) kunye nokungathandi iziyobisi (p <0.05).
Iziphumo zokuziphatha zeMP emithanjeni kulawulo kunye nezifundo ezinxilisayo kunye F amaxabiso e-factorial ephindaphindwayo ye-ANOVA yeqela, ichiza, kunye neziphumo zokusebenzisana
I-MP yandisa izinga lentliziyo kunye ne-systolic kunye ne-diastolic yegazi, kwaye ezi ziphumo azizange zihluke phakathi kwamaqela (idatha engaboniswa).
Amanyathelo eDA D2/D3 ukufumaneka kwe-receptor kwisiseko (placebo)
Kwisiseko, kwakungekho yantlukwano K1 phakathi kwamaqela kwicerebellum, CDT, PUT, okanye VS (3 Table). Ngokwahlukileyo, D2/D3 ukufumaneka kwe-receptor (Bmax''/Kd') ibonise isiphumo esibalulekileyo seqela kwi-VS (p <0.007) kodwa akukho mahluko kwi-CDT kunye ne-PUT. Ngeposi t uvavanyo lubonise ukuba VS D2/D3 ukufumaneka kwe-receptor kwakuphantsi kakhulu kwiinxila (p <0.05) (3 Table).
Imilinganiselo ye K1 kwaye Bmax''/Kd' ukwenzela i [11C]imifanekiso yeraclopride yolawulo kunye nezifundo ezinxilisayo kwi-placebo (PL) kunye neemeko zeMP, kunye ne p amaxabiso eziphumo ze-ANOVA zeqela, ichiza, kunye neziphumo zentsebenziswano
Amanyathelo eDA D2/D3 ukufumaneka kwe-receptor emva kweMP (utshintsho lweDA)
ANOVA kwi K1 amanyathelo abonise ukuba akukho machiza okanye imiphumo yokusebenzisana yayibalulekile kwi-CDT, i-PUT, i-VS, okanye i-cerebellum, ebonisa ukuba i-MP ayizange itshintshe ukuhanjiswa kwe-radiotracer kwaye akukho mahluko phakathi kwamaqela.3 Table).
I-MP yehla Bmax''/Kd', kwaye i-ANOVA iveze isiphumo esibalulekileyo sechiza kwi-CDT (F = 19; p < 0.001), PUT (F = 54; p < 0.0001), kunye ne-VS (F = 41; p <0.001), nto leyo ebonisa ukuba Bmax''/Kd’ yacuthwa kakhulu yiMP kuwo omabini amaqela (bona Ikhiwane. 2, 3 Table). Isiphumo sokusebenzisana sasibalulekile kwi-PUT (F = 5.5; p < 0.03) kunye ne-VS (F = 13; p <0.001), ebonisa ukuba iimpendulo kule mimandla zahluke phakathi kwamaqela. I iposi hoc t uvavanyo lubonise ukuba ukuncitshiswa kwe-MP kuncinci kakhulu kutywala kwi-PUT (ulawulo, i-21% vs izinxila, i-11%; p <0.03) kunye ne-VS (ulawulo, i-27% vs izinxila, i-8%; p <0.002) (Ikhiwane. 1, 3 Table).
I-avareji yomlinganiselo we-DV (DVR) imifanekiso ye [11C]raclopride yolawulo (n = 20) kunye neenxila (n = 20) kwinqanaba le-striatum emva kwe-placebo nasemva kweMP. Qaphela ukuhla kokubophelela okuthe ngqo (i-DV ratios) kunye neMP kunye nempendulo ethotyiweyo kwiMP kwizifundo ezinxilisayo xa kuthelekiswa nolawulo.
Ukuvavanya ukuba ingaba encinci iyatshintsha na Bmax''/Kd’ (I-PUT kunye ne-VS) kwiinxila kunezolawulo zibonakalise inani elikhulu labantu abatshayayo, sathelekisa abatshayayo abangatshayiyo ngokwahlukeneyo kwiqela ngalinye saza sabonisa oku kulandelayo: (1) abalawuli abatshayayo (n = 3) babenotshintsho olufanayo kunabo bangazange (n = 17) kwi-PUT (20 vs 21%, ngokulandelanayo) kunye ne-VS (35 vs 26%, ngokulandelanayo); kunye (2) namanxila atshayayo (n = 16) babenotshintsho olufanayo kunabo bangazange (n = 4) kwi-PUT (11 vs 12%, ngokulandelanayo) kunye ne-VS (8 vs 6%, ngokulandelanayo).
Nangona iisampulu zincinci kakhulu ukuba zingavelisa iziphumo eziqinisekileyo, akukho nanye kolu thelekiso ibe lutshintsho Bmax''/Kd′ bancinci kwiintshayi, nto leyo ebonisa ukuba utshintsho oluncinane kumakhoboka otywala alubangelwa nje kukutshaya.
Ingqondo yengingqi ye-glucose metabolism kunye nokulungelelaniswa notshintsho olwenziwe yiMP kwi Bmax''/Kdkunye nemilinganiselo esisiseko ye-D2 ukubakho kwe-receptor
Akukho ngqondo-bonke (ulawulo, 36.4 ± 4 μmol/100 g/min; izinxila, 35.0 ± 4 μmol/100 g/min) okanye imetabolism yommandla yahluka phakathi kwamaqela (idatha ayiboniswanga).
Kulawulo, utshintsho olwenziwe yiMP kwi Bmax''/Kd’ kwi-VS zayanyaniswa kakubi nemetabolism kwi-OFC [indawo kaBrodmann (BA) 11: r = 0.62, p < 0.006; BA 47: r = 0.60, p < 0.008], DLPFC (BA 9: r = 0.59, p < 0.01), CG (BA 32: r = 0.50 p < 0.04; BA 24: r = 0.52, p <0.03), kunye ne-insula (r = 0.63; p < 0.005). (Ikhiwane. 2). Bmax''/KdIinguqu kwi-CDT kunye ne-PUT zihambelana kuphela ne-metabolism kwi-CG.r >0.51; p < 0.03). Kwizinxila, ulungelelwaniso phakathi kweMP-induced change in Bmax''/Kdkunye nemetabolism yengingqi ayibalulekanga (Ikhiwane. 2). Ukuthelekiswa kwethambeka lokubuyela umva phakathi kwamaqela kubonise ukuba ulungelelwaniso lwahluke kakhulu kwi-OFC (z = 2.3; p < 0.05), DLPFC (z = 2.2; p <0.05), CG (z = 2.2; p <0.05), kunye ne-insula (z = 2.6; p <0.01).
Ukuhlehla kwethambeka phakathi kotshintsho lwepesenti kwi Bmax''/Kd’ (utshintsho oluxhomekeke) kwi-VS kunye nomsebenzi opheleleyo we-metabolism yobuchopho bengingqi kwi-OFC (BA 11), i-CG yangaphambili (BA 32), kunye ne-DLPFC (BA 9) kulawulo (izangqa ezizeleyo) nakwizinxila (iizangqa ezivulekileyo). Qaphela ukuba ipesenti iyancipha kwisibophelelo esithile se [11C]raclopride (Bmax''/Kd') bonisa ukunyuka kwe-DA ehambelanayo, kwaye ke ukuhlehliswa kudlulisa ulungelelwaniso olubi: i-metabolism ephantsi, i-DA iyanda.
Ulungelelwaniso kunye nemilinganiselo ye-metabolism eqhelekileyo (ingingqi / yonke ingqondo yemetabolism) yayibalulekile kuphela kutshintsho phakathi Bmax''/Kdkwi-VS kunye ne-OFC (r = 0.62; p <0.006) kulawulo kodwa hayi kwiinxila (Ikhiwane. 3). Olu nxulumano lwahluke kakhulu phakathi kwamaqela (z = 2.1; p <0.05).
Unxulumano kunye nesiseko Bmax''/Kd"(D2 ukufumaneka kwe-receptor) kunye ne-metabolism yengingqi yayibalulekile kubantu abanxilisayo kodwa kungekhona ulawulo kwi-CG (CDT: r = 0.57, p < 0.02; BEKA: r = 0.59, p < 0.01; VS: r = 0.57, p < 0.02) kunye ne-DLPFC (CDT: r = 0.52, p < 0.03; BEKA: r = 0.52, p < 0.03; VS: r = 0.50, p <0.03).
Unxulumano phakathi kweenguqu ezenziwe yiMP kwi Bmax''/Kd' kunye neziphumo zayo zokuziphatha kunye nokusela kunye nembali yokutshaya
Utshintsho kwi Bmax''/Kdkwi-VS ehambelana nokuphezulu (r = 0.40; p <0.01), iziyobisi zilungile (r = 0.33; p <0.05), ndonwabile (r = 0.33; p <0.05), ukungazinzi (r = 0.38; p <0.02), kwaye ivuselelwe (r = 0.45; p < 0.005); kwi-PUT ephezulu (r = 0.32; p <0.05), iziyobisi zilungile (r = 0.34; p <0.05), kwaye ivuselelwe (r = 0.46; p < 0.005); kunye ne-CDT evuselelwe (r = 0.32; p <0.05).
Ukuhlehla kwethambeka phakathi kotshintsho lwepesenti kwi Bmax''/Kd(ukuxhomekeka okuguquguqukayo) kwi-VS kunye nomsebenzi oqhelekileyo we-metabolic kwi-OFC (ingqondo yonke) kulawulo (izangqa ezizalisweyo) nakwizinxila (iizangqa ezivulekileyo).
Ayinambali yotywala okanye yokutshaya ehambelana notshintsho Bmax''/Kd’ xa onke amanxila ayequkiwe. Nangona kunjalo, xa kuphela izinxila ezitshayayo zahlalutywayo, kukho ulungelelwaniso olubalulekileyo phakathi kotshintsho Bmax''/Kd' kunye neminyaka yokutshaya (PUT: r = 0.73, p <0.002) kunye nobudala bokuqalisa ukutshaya (PUT: r = 0.63, p < 0.009; VS: r = 0.53, p <0.05).
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Ulawulo lwangaphambili lwe-MP-eyenziwe yi-DA utshintsho kulawulo kodwa hayi kwiinxila
Kulawulo, sibonisa unxibelelwano olungalunganga phakathi komsebenzi opheleleyo we-metabolic kwimimandla yangaphambili (OFC, CG, DLPFC) kunye notshintsho olwenziwe yiMP kwi. Bmax''/Kd(uqikelelo lweenguqu zeDA) kwi-VS kunye ne-PUT. Ngaphaya koko, olu lungelelwaniso lwahlala kwi-OFC emva kokuqhelaniswa nomsebenzi we-metabolism yengqondo epheleleyo ebonisa ukuba, ubuncinci kwi-OFC, icacisiwe ngokwengingqi. Oku kufunyanisiweyo kuyahambelana nezifundo zangaphambi kweklinikhi ezibhala ukulawulwa kwangaphambili kweeseli ze-DA kwi-VTA kunye nokukhutshwa kwe-DA kwi-NAc (IGariano kunye neeGroves, i-1988; UMurase et al., 1993).
Ngokwahlukileyo kwizinxila, i-metabolism kwimimandla yangaphambili ayizange idityaniswe neenguqu ze-DA (njengoko kuvavanywa ngotshintsho kwi-DA). Bmax''/Kd′). Oku kuphakamisa ukuba kwiinxila, ukulawulwa komsebenzi weseli ye-DA nge-prefrontal efferents kuyaphazamiseka kwaye ukuncipha komsebenzi wabo weseli ye-DA kunokumela ilahleko yolawulo lwangaphambili lweendlela ze-DA mesolimbic. Elinye lamagalelo aphambili kwiiseli ze-DA kwi-VTA yi-glutamatergic efferents evela kwi-prefrontal cortex (UCarr noSesack, ngo-2000), kwaye kukho ubungqina obukhulayo bokuba badlala indima ebalulekileyo kumlutha (IKalivas neVolkow, i-2005). Izifundo zangaphambi kweklinikhi zikwabonise ukuba impembelelo ye-prefrontal cortex kulawulo lokuziphatha iyancipha ngolawulo lweziyobisi ezingapheliyo ezinegalelo ekuphulukaneni nolawulo kubukhoboka (Homayoun kunye noMoghaddam, ngo-2006). Ngaphaya koko, ukuphazamiseka kwe-OFC (ingingqi ebandakanyeka kuphawu olubalulekileyo, ukuphazamiseka kwayo okunxulunyaniswa nokuziphatha okunyanzelekileyo) kunye ne-CG (ingingqi ebandakanyeka kulawulo lokuthintela, ukuphazamiseka kwayo okuyanyaniswa nokungabinamdla) kuthathwa njengeyona nto iphambili kwinkqubo yokulutha.Volkow et al., 2003).
Uhlalutyo lokuphonononga lubonise ukuba kulawulo, utshintsho lwe-DA kwi-VS luye lwahambelana ne-metabolism kwi-insula. I-insula yenye yemimandla yecortical enowona mmandla uxineneyo weDA (I-Gaspar et al., 1989), kunye nophononongo lwakutsha nje olunika ingxelo yokuba umonakalo kwi-insula elungileyo yadityaniswa nokuyeka ukutshaya ngokukhawuleza kubalaselisa ukubaluleka kwayo kumlutha (Naqvi et al., 2007).
Ukunciphisa ukukhutshwa kwe-DA kwizifundo ezinxilisayo
Kwizinxila, i-MP yenza ukwanda okuncinci kwe-DA kwi-VS kunye ne-PUT kunolawulo. MP yi-blocker ye-DAT, kwaye kwinqanaba elinikiweyo le-DAT blockade, utshintsho lwe-DA lubonisa inani le-DA ezenzekelayo ekhutshwe (Volkow et al., 1999). Ngenxa yokuba ukuxinwa kweMP kwiplasma, engazange yahluke phakathi kwamaqela, iqikelela amanqanaba e-DAT blockade (Volkow et al., 1998, 1999), impendulo ephosakeleyo kwi-MP ibonisa ukuba izinxila zine-DA ephantsi yokukhululwa kunolawulo. Ukunciphisa kwakugxininiswe kakhulu kwi-VS (i-70% ephantsi kunolawulo), eqinisekisa iziphumo zangaphambili zokunciphisa i-DA ukunyuka kwe-VS emva kwe-amphetamine kwizinxila (i-50% ephantsi kunolawulo) (UMartinez et al., 2005). Ezi ziphumo zikwavumelana nezifundo zangaphambi kweklinikhi ezibonisa ukuncipha okunzulu ekudubuleni kweeseli zeDA (UDiana et al., 1993; Bailey et al., 1998; Shen et al., 2007) kwi-VTA kwaye yehla i-DA kwi-NAc (Weiss et al., 1996) emva kokuyeka utywala obungapheliyo. Ukuncipha kokuphinda kusebenze kwakhona kwe-DA VTA-eqokelela indlela kumakhoboka otywala kunokubabeka emngciphekweni wokusela izixa ezikhulu zotywala ukuhlawula le ntsilelo. Enyanisweni, ulawulo lotywala olubukhali lubuyisela umsebenzi weeseli ze-VTA DA kwizilwanyana eziphathwa ngokungapheliyo ngotywala (UDiana et al., 1996; Weiss et al., 1996).
Izinxila zikwabonise ukonyuka okwenziwa buthuntu kweDA okubangelwa yiMP kwiPUT (ama-47% ngaphantsi kunolawulo). Oku kubonakalisa ukubandakanyeka kweeseli ze-DA kwi-substantia nigra, iprojekthi ye-PUT kwaye ibandakanyeka kukuziphatha kwemoto. Ukusilela kwe-DA kwi-PUT kunokuchaza umngcipheko omkhulu weempawu zemoto ye-extrapyramidal kubantu abanxilisayo (Shen, 1984).
Izifundo zangaphambili kubaxhaphazi be-cocaine zikwabhale ukuncitshiswa okubalulekileyo kwe-MP-induced DA ukunyuka (i-50% ephantsi kunolawulo) (Volkow et al., 1997), ecebisa ukuba ukuncipha komsebenzi weseli ye-DA kunokubonisa ukungaqhelekanga okuqhelekileyo kubukhoboka.
Ukunciphisa iimpendulo zokuqinisa kwi-MP ye-intravenous kwiinxila
Iimpendulo ezivuzayo kwi-MP kwinxila zaziphantsi kunolawulo. Inyani yokuba ezi ziphumo zeMP yayanyaniswa nokunyuka kwe-DA kwi-VS icebisa ukuba iimpendulo eziqinisiweyo ezibethelelweyo kwiMP zibonisa ukuncipha komsebenzi weseli ye-VTA yeDA. Ukuya kuthi ga kwinqanaba lokuba iiseli ze-VTA DA, ngokuyinxenye ngokuqikelelwa kwazo kwi-NAc, zibandakanyeka ekumodareyitheni iimpendulo ezomelezayo kwii-nondrug reinforcers ezinciphisa umsebenzi weseli ye-DA zinokuthoba ubuntununtunu obuncitshisiweyo kwimbuyekezo engeyiyo yotywala kwizinxila.Cima et al., 2007).
Utywala / inikotini ehambelanayo
Kwizifundo ezinxilisayo ezazitshaya, iinguqu ze-DA ezenziwe yiMP zazinxulunyaniswa nembali yabo yokutshaya. Lo mbutho unokubonakalisa iimpendulo eziqhelekileyo zokuziqhelanisa notywala kunye necuba kuba i-nicotine engapheliyo ikwanciphisa umsebenzi ozenzekelayo weeseli ze-VTA DA (ULiu noJin, ngo-2004). Nangona kunjalo, ngenxa yokuba utshintsho lwe-DA aluzange luhluke phakathi kwabatshayayo abanxilisayo kunye nabo bangatshayiyo naphakathi kwabatshayayo kunye nabangatshayiyo, akunakwenzeka ukuba ukuncitshiswa kwe-DA kubangelwe nje kukutshaya kodwa kunokubonakalisa ubuthathaka obuqhelekileyo.Yinyani et al., 1999; Bierut et al., 2004; I-et et., 2006).
Isiseko seDA D2/D3 amanyathelo amamkeli
Isiseko seDA D2/D3 ukufumaneka kwe-receptor bekusezantsi kwizinxila kunezolawulo kwi-VS, eqinisekisa umfanekiso wangaphambili (UHeinz et al., 2004; Shen et al., 2007) kunye ne-postmortem (Tupala et al., 2001, 2003) izifundo.
Isiseko D2/D3 ukufumaneka kwe-receptor kwi-alcohols (kodwa kungekhona kulawulo) yayinxulumene ne-metabolism kwi-CG kunye ne-DLPFC. Oku kuyahambelana neziphumo zangaphambili kwi-cocaine kunye nabaxhaphazi be-methamphetamine nakwizifundo ezisengozini enkulu yemfuza yokusela utywala apho siphinde sanika ingxelo yobudlelwane phakathi kwesiseko sokulala D.2/D3 ukufumaneka kwe-receptor kunye ne-prefrontal metabolism (Volkow et al., 1993b, 2001, 2006). Nangona kunjalo, iyaphikisana nokulungelelaniswa phakathi kwe-metabolism yangaphambili kunye neenguqu ze-DA ezenziwe yi-MP, ezazibalulekile kulawulo kodwa kungekhona kwiinxila. Oku kunokwenzeka ukuba kubonise into yokuba zihambelana nemilinganiselo eyahlukeneyo ye-DA neurotransmission; utshintsho kwi Bmax''/Kdbonisa ukukhutshwa kwe-DA kwi-neurons ye-DA, engumsebenzi wokudubula kweeseli ze-DA kwaye imodareyithwe ngumsebenzi wangaphambili, ngelixa uD2/D3 ukufumaneka kwe-receptor ubukhulu becala kubonakalisa amanqanaba e-receptor ekucingelwa ukuba ahlengahlengiswa yimiba yemfuza kunye ne-epigenetic kodwa, kulwazi lwethu, hayi ngomsebenzi wangaphambili. Ke ngoko, unxibelelwano phakathi kwesiseko seD2/D3 ii-receptors zinokubonisa ukumodareyitha kwe-dopaminergic kwimimandla ye-cortical yangaphambili (I-Ods kunye neHolide, i-1987). Enyanisweni, kwiziselo ezinxilisayo, ukuncitshiswa kokufumaneka kwe-D2R kwi-VS kubonakaliswe kunxulunyaniswa nobunzima bokunqwenela utywala kunye nokusebenza okukhulu kwe-cue-induced cortex ye-medial prefrontal cortex kunye ne-CG yangaphambili njengoko ihlolwe nge-imaging magnetic resonance imaging.UHeinz et al., 2004).
Isiseko sommandla wengqondo ye-glucose metabolism
Kule sifundo, asizange sibonise ukungafani kwi-brain glucose metabolism (kubandakanywa ne-cortex yangaphambili) phakathi kokulawula kunye nezinxila. Oku kwahluka kwizifundo zangaphambili, ezibonise ukunciphisa kwi-metabolism yangaphambili kwi-alcohols (uphononongo, bona Wang et al., 1998). Nangona kunjalo, ngenxa yokuba ukunciphisa kwi-metabolism yengqondo kubuyisela kakhulu kwiiveki ze-2-4 ze-detoxification (ingakumbi kwi-cortex yangaphambili)Volkow et al., 1994b), ukungaphumeleli ekuboneni ukunciphisa kwizifundo zethu kungabonakalisa into yokuba baye bahoxisa utywala ubuncinane kwi-30 d ngaphambi kophando.
Imida
Okokuqala, ngenxa yokuba [18F]FDG, inesiqingatha sobomi be-120 min, kwakungenakwenzeka ukwenza [11C] imilinganiselo ye-raclopride ngosuku olufanayo (iiyure eziyi-10 ziyafuneka phakathi kweenaliti). Nangona kunjalo, ngenxa yokuba isiseko semilinganiselo yobuchopho bengingqi kunye nemilinganiselo ye-MP-induced DA utshintsho luzinzile xa izifundo zivavanywa ngeentsuku ezahlukeneyo (U-Wang et al., 1999a,b), ulungelelwaniso lunokuba lufana nokuba bekunokwenzeka ukuba kuvavanywe kwangolo suku lunye.
Okwesibini, ulungelelwaniso kunye ne-CG, i-DLPFC, kunye ne-insula yayingabalulekanga xa umsebenzi wawuqhelekile kwi-metabolism yengqondo epheleleyo, ngoko ke kule mimandla, imibutho kufuneka ithathelwe ingqalelo njengeyokuqala. Kwakhona, ulungelelwaniso aluthethi ukuba umanyano lwe-causal alubonisi umkhombandlela kwaye ngenxa yoko asinakumisela ukuba umbutho endaweni yokubonisa umgaqo wangaphambili wokukhutshwa kwe-DA ubonisa ukumodareyithwa kweDA kwemimandla yangaphambili.
Okwesithathu, isiseko esincitshisiweyo D2/D3 ukufumaneka kwe-receptor xa kulinganiswa nge [11I-C]raclopride inokubonakalisa amanqanaba aphantsi e-receptor okanye ukwanda kokukhululwa kwe-DA (Gjedde et al. 2005). Nangona kunjalo, into yokuba abanxila, xa benikwe iMP, babonise ukukhutshwa kwe-DA okuncitshisiweyo kubonisa ukuba amanyathelo asezantsi esiseko se-D2/D3 ukufumaneka kwe-receptor kwiinxila zibonakalisa, njengoko kuchazwe ngaphambili ngezifundo ze-postmortem (Tupala et al., 2003), amanqanaba aphantsi e-D2 zamkeli.
Okokugqibela ukutshaya kubhidekile, kodwa ngenxa yokuba ama-90% abantu abanxila bayatshaya (Batel et al., 1995), iziphumo zethu zihambelana neklinikhi kuninzi lwabanxila.
isiphelo
Ezi ziphumo ziyahambelana ne-hypothesis yokulahleka kwe-prefrontal modulation yomsebenzi weseli ye-DA kwizinxila kunye nokuncipha okukhulu komsebenzi we-DA kwezi zifundo. Ubudlelwane phakathi kokunyuka kwe-DA ebolileyo kwi-VS kunye nokuncitshiswa kweempendulo ezivuzayo kwi-MP icebisa ukuba izinto ezingaqhelekanga ze-DA zinokuthi zibe phantsi kwe-anhedonia efunyanwa ngabanxilisayo kwaye kunokuba negalelo kumngcipheko wabo wokusetyenziswa kakubi kotywala njengendlela yokuhlawula le ntsilelo. Ezi ziphumo zibonisa ukuba ungenelelo lokubuyisela ulawulo lwangaphambili kunye nentsilelo ye-DA inokuba luncedo ngonyango kwiinxila.
Imihlathi
- I funyenwe Julayi 25, 2007.
- Uhlaziyo olufunyenweyo Oktobha 2, 2007.
- Zamkelwa Oktobha 2, 2007.
Lo msebenzi uxhaswe ngokuyinxenye yiNkqubo yoPhando lwe-Intramural yeZiko leSizwe lezeMpilo-iZiko leSizwe loTywala kunye nokuSetyenziswa kakubi koTywala, liSebe lezaMandla (i-Ofisi ye-Biological and Environmental Research, ikhontrakthi DE-AC01-76CH00016), kunye neSizwe. Iziko leSibonelelo seMpilo yengqondo MH66961-02. Siyabulela uDonald Warner ngemisebenzi ye-PET; UDavid Schlyer noMichael Schueller kwimisebenzi ye-cyclotron; UDavid Alexoff kunye noPaul Vaska wokulawula umgangatho wamanyathelo e-PET; Colleen Shea, Lisa Muench, kunye Youwen Xu for radiotracer synthesis; UPauline Carter kukhathalelo lokonga; UKaren Apelskog wolungelelwaniso lweprotocol; kunye noLinda Thomas ngoncedo lokuhlela.
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Ucaphulo
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